Unlike type 2 diabetes, where prevention is possible, type 1 diabetes is currently neither preventable nor curable and its incidence continues to rise approximately 3% per year. Thus, the continuing investigation of type 1 diabetes complications remains imperative. The Epidemiology of Diabetes Complications (EDC) study has examined the prevalence and incidence of and risk factors contributing to the diabetes complications for 20 years. The study population is a well defined cohort of childhood onset type 1 diabetes identified from the Children's Hospital of Pittsburgh Registry (diagnosis: 1950-80). All 658 participants attending a clinical exam at study entry (1986-88) have been subsequently followed for up to 20 years, leading to over 114 peer reviewed publications. A number of striking preliminary observations made during the last phase of the study have given rise to questions and hypotheses this renewal aims to address. These include the increasingly complex interaction between various pro- and anti-glycoxidative and inflammatory cytokines, as well as the rapidly changing natural history of complications which provides further insight into the interrelationships of, and specific risk factors for, complications, and renders historic data outdated for health care and insurance purposes. The current application, therefore, focuses on further assessment of complication development for a total follow up period of 25 years, thus allowing reasonably stable estimates of complication development over 40 years duration of childhood onset type 1 diabetes. This gives the opportunity to document morbidity risk and to estimate life expectancy in the modern era, i.e. for those diagnosed in 1965-80 and who have had more than half their diabetes duration since the availability of HbA1c testing and self monitoring of blood glucose. The roles of glycemic, oxidative and inflammatory stress, and the host's responses they invoke, on complication development will be another major focus along with women's health issues and continuing a number of collaborations. Finally, we will evaluate skin advanced glycosylation end products using a new instrument and how they relate to complication risk. This will be facilitated by continuing the annual surveys and, at 25 years of follow up, a full examination. PUBLIC HEALTH RELEVANCE: The significance of this application lies in the ability to provide, in a large type 1 diabetes cohort, documentation of morbidity risk and estimates of life expectancy in the modern era of HbA1c testing and self monitoring of blood glucose, whereas the availability of stored specimen offers the opportunity to address the role of stress (glycemic, oxidative and/or inflammatory) and the host's response it provokes, in the pathogenesis of vascular complications. This application also addresses women's health issues and evaluates new instruments in their ability to predict complication risk. As currently type 1 diabetes is neither preventable nor curable, the continuing investigation of its complications remains imperative and the present study may both further our knowledge of the natural history of complications and also point to novel approaches to prevention and management.